Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABA A receptors, which are members of the ligand-gated ion channel superfamily and (2) GABA B receptors, which are members of the G-protein linked receptor family. The GABA A receptor complex which is a membrane-bound heteropentameric protein polymer is composed principally of α, β and γ subunits. Presently a total number of 21 subunits of the GABA A receptor have been cloned and sequenced. Three types of subunits (α, β and γ) are required for the construction of recombinant GABA A receptors which most closely mimic the biochemical, electrophysiological and pharmacological functions of native GABA A receptors obtained from mammalian brain cells. There is strong evidence that the benzodiazepine binding site lies between the α and γ subunits. Among the recombinant GABA A receptors, α1β2γ2 mimics many effects of the classical type-I benzodiazepine receptor (BzR) subtypes, whereas α2β2γ2, α3β2γ2 and α5β2γ2 ion channels are termed type-II BzR(R. M. McKernan, P. J. Whiting, in Recombinant Cell Surface Receptors: Focal Point for Therapeutic Intervention, M. J. Browne (Ed.) (1997) Chapter 8:155-173, R. G. Landes Co., Austin, Tex.).
It has been shown by McNamara and Skelton (Psychobiology (1993) 21:101-108) that the benzodiazepine receptor inverse agonist β-CCM enhance spatial learning in the Morris watermaze. However, β-CCM and other conventional benzodiazepine receptor inverse agonists are proconvulsant or convulsant which prevents their use as cognition enhancing agents in humans. In addition, these compounds are non-selective within the GABA A receptor subunits, whereas a GABA A α5 receptor partial or full inverse agonist which is relatively free of activity at GABA A α1 and/or α2 and/or α3 receptor binding sites can be used to provide a medicament which is useful for enhancing cognition with reduced or without proconvulsant activity. It is also possible to use GABA A α5 inverse agonists which are not free of activity at GABA A α1 and/or α2 and/or α3 receptor binding sites but which are functionally selective for α5 containing subunits. However, inverse agonists which are selective for GABA A α5 subunits and are relatively free of activity at GABA A α1, α2 and α3 receptor binding sites are preferred.
Literature has been published to establish the link between GABA A α5 subunits and the treatment of various diseases of the Central Nervous System (Neuroscience Letts. (2005) 381:108-13, Neuropsychobiology (2001) 43(3):141-44, Amer. J. Med. Genetics (2004) 131B:51-9, Autism (2007) 11(2):135-47, Investigacion Clinica (2007) 48:529-41, Nature Neuroscience (2007) 10:411-13, Neuroscience Letts. (2008) 433: 22-7, Cell (2008) 135:549-60).